title: Altered protein prenylation in Sertoli cells is associated with adult infertility resulting from childhood mumps infection.
abstract: Mumps commonly affects children 5-9 yr of age, and can lead to permanent adult sterility in certain cases. However, the etiology of this long-term effect remains unclear. Mumps infection results in progressive degeneration of the seminiferous epithelium and, occasionally, Sertoli cell-only syndrome. Thus, the remaining Sertoli cells may be critical to spermatogenesis recovery after orchitis healing. Here, we report that the protein farnesylation/geranylgeranylation balance is critical for patients' fertility. The expression of geranylgeranyl diphosphate synthase 1 (GGPPS) was decreased due to elevated promoter methylation in the testes of infertile patients with mumps infection history. When we deleted GGPPS in mouse Sertoli cells, these cells remained intact, whereas the adjacent spermatogonia significantly decreased after the fifth postnatal day. The proinflammatory MAPK and NF-κB signaling pathways were constitutively activated in GGPPS(-/-) Sertoli cells due to the enhanced farnesylation of H-Ras. GGPPS(-/-) Sertoli cells secreted an array of cytokines to stimulate spermatogonia apoptosis, and chemokines to induce macrophage invasion into the seminiferous tubules. Invaded macrophages further blocked spermatogonia development, resulting in a long-term effect through to adulthood. Notably, this defect could be rescued by GGPP administration in EMCV-challenged mice. Our results suggest a novel mechanism by which mumps infection during childhood results in adult sterility.
authors.affiliation: MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and Jiangsu Key Laboratory of Molecular Medicine of the School of Medicine, Nanjing University, National Resource Center for Mutant Mice, Nanjing 210061, China.
authors.forename: Xiu-Xing
authors.initials: XX
authors.lastname: Wang
authors.forename: Pu
authors.initials: P
authors.lastname: Ying
authors.forename: Fan
authors.initials: F
authors.lastname: Diao
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.forename: Dan
authors.initials: D
authors.lastname: Ye
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
authors.forename: Ning
authors.initials: N
authors.lastname: Shen
authors.forename: Na
authors.initials: N
authors.lastname: Xu
authors.forename: Wei-Bo
authors.initials: WB
authors.lastname: Chen
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Lai
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Miao
authors.forename: Jin
authors.initials: J
authors.lastname: Feng
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Tao
authors.forename: Ning-Wei
authors.initials: NW
authors.lastname: Zhao
authors.forename: Bing
authors.initials: B
authors.lastname: Yao
authors.forename: Zhi-Peng
authors.initials: ZP
authors.lastname: Xu
authors.forename: Hai-Xiang
authors.initials: HX
authors.lastname: Sun
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Li
authors.forename: Jia-Hao
authors.initials: JH
authors.lastname: Sha
authors.forename: Xing-Xu
authors.initials: XX
authors.lastname: Huang
authors.forename: Qing-Hua
authors.initials: QH
authors.lastname: Shi
authors.forename: Hong
authors.initials: H
authors.lastname: Tang
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Chao-Jun
authors.initials: CJ
authors.lastname: Li
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002648:Child; D016207:Cytokines / Q000096:biosynthesis; D019175:DNA Methylation; D051231:Farnesyltranstransferase / Q000235:genetics; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007248:Infertility, Male / Q000209:etiology* / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009107:Mumps / Q000150:complications*; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017368:Protein Prenylation / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D012671:Seminiferous Tubules / Q000473:pathology; D012708:Sertoli Cells / Q000378:metabolism*; D013093:Spermatogonia / Q000378:metabolism / Q000473:pathology; D013737:Testis / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D051231:Farnesyltranstransferase; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras)